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Amrubicin API Manufacturers & Suppliers

General Description:

Amrubicin, identified by CAS number 110267-81-7, is a notable compound with significant therapeutic applications. Amrubicin is a third-generation synthetic anthracycline currently in development for the treatment of small cell lung cancer. Pharmion licensed the rights to Amrubicin in November 2006. In 2002, Amrubicin was approved and launched for sale in Japan based on Phase 2 efficacy data in both SCLC and NSCLC. Since January 2005, Amrubicin has been marketed by Nippon Kayaku, a Japanese pharmaceutical firm focused on oncology, which licensed Japanese marketing rights from Dainippon Sumitomo, the original developer of Amrubicin .

Indications:

This drug is primarily indicated for: Investigated for use/treatment in lung cancer . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Amrubicin undergoes metabolic processing primarily in: The primary metabolite (amrubicinol) in rats and dogs is a product of reduction by cytoplasmic carbonyl reductase at the C-13 carbonyl group. Other enzymes participating in the metabolism of amrubicin and amrubicinol were nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)–P450 reductase and nicotinamide adenine dinucleotide (NADH)-quinone oxidoreductase. Twelve additional metabolites were detected in vivo and in vitro in one study . Peak plasma concentrations of the active metabolite amrubicinol were observed from immediately after dosing to 1 hour after dosing . These included four aglycone metabolites, two amrubicinol glucuronides, deaminated amrubicin, and five highly polar unknown metabolites. In vitro cell growth inhibitory activity of the minor metabolites was substantially lower than that of amrubicinol. Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Amrubicin are crucial for its therapeutic efficacy: Peak plasma concentrations of the active metabolite _amrubicinol_ were observed from immediately after administration of amrubicin to 1h after administration. Plasma concentrations of amrubicinol were low compared with amrubicin plasma concentrations. The plasma amrubicinol AUC (area under the curve) was approximately 10-fold lower than the amrubicin plasma AUC. Concentrations of amrubicinol were higher in RBCs as compared with plasma. Amrubicinol AUCs ranged from 2.5-fold to 57.9-fold higher in red blood cells (RBCs) compared to plasma. Because amrubicinol distributes itself into RBCs more than amrubicin, the concentrations of amrubicinol and amrubicin in RBCs were quite similar. The AUC of amrubicinol in RBCs was approximately twofold lower than the amrubicin RBC AUC . In one study, after repeated daily amrubicin administration, amrubicinol accumulation was observed in plasma and RBCs. On day 3, the amrubicinol plasma AUC was 1.2-fold to 6-fold higher than day 1 values; the RBC AUC was 1.2-fold to 1.7-fold higher than day 1 values. After 5 consecutive daily doses, plasma and RBC amrubicinol AUCs were 1.2-fold to 2.0-fold higher than day 1 values . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Amrubicin is an important consideration for its dosing schedule: 20-30 h In a study of dogs, Amrubicin plasma concentrations followed a biphasic pattern with peak concentrations observed immediately after dosing followed by α and β half-lives (t1/2) ± SD of 0.06 ± 0.01 and 2.0 ± 0.3 hours, respectively . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Amrubicin exhibits a strong affinity for binding with plasma proteins: A study was performed on the plasma protein binding of amrubicin in both patients with hepatic impairment and those with normal liver function. In those with liver impairment, the plasma protein binding was found to be 91.3–97.1% and in those with normal hepatic function, 82.0–85.3% . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Amrubicin from the body primarily occurs through: In one study, urinary excretion of amrubicin and amrubicinol after ingestion of amrubicin accounted for 2.7% to 19.6% of the administered dose. The amount of excreted amrubicinol was approximately 10-fold greater than excreted amrubicin . Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Amrubicin is distributed throughout the body with a volume of distribution of: Moderate volume of distribution (1.4 times total body water) . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Amrubicin is a critical factor in determining its safe and effective dosage: The plasma pharmacokinetics of amrubicin in cancer patients are characterized by low total clearance (22% of total liver blood flow) . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Amrubicin exerts its therapeutic effects through: The _anthracycline glycoside_ group of antibiotics, which includes amrubicin, represent a group of potent anticancer agents with potent activity against both solid tumors and hematological malignancies. They are the principal subjects of a large number of studies for the treatment of adult and childhood neoplastic diseases . Amrubicin is a 9-aminoanthracycline derivative and promotes cell growth inhibition by stabilizing protein – DNA complexes followed by double-stranded DNA breaks, which are mediated by topoisomerase-II enzyme . Anthracyclines have been observed to have a variety molecular effects (for example, DNA intercalation, inhibition of topoisomerase II, and stabilization of topoisomerase IIα cleavable complexes). Amrubicin shows decreased DNA intercalation when compared with doxorubicin. The decreased DNA interaction likely influences the intracellular distribution because amrubicin and its metabolite, _amrubicinol_. Amrubicin showed 20% distribution into the nucleus of P388 cells compared with the 80% nuclear distribution shown by doxorubicin (another anthracycline drug). The cell growth inhibitory effects of amrubicin appear to be mainly due to the inhibition of topoisomerase II . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Amrubicin functions by: As an anthracycline, amrubicin has antimitotic and cytotoxic activity through a variety of mechanisms of action. Amrubicin is found to form complexes with DNA via intercalation between base pairs, and it inhibits topoisomerase II enzyme activity by stabilizing the DNA-topoisomerase II complex, which prevents the re-ligation portion of the ligation-religation reaction that topoisomerase II normally catalyzes . Topoisomerase II is an enzyme located in the nucleus that regulates DNA structure through double-strand breakage and re-ligation, therefore modulating DNA replication and transcription. Inhibition of the enzyme leads to inhibition of DNA replication and halt cell growth with an arrest of the cell cycle occurring at the G2/M phase. The mechanism by which amrubicin inhibits DNA topoisomerase II is believed to be through stabilization of the cleavable DNA–topo II complex, ending in re-ligation failure and DNA strand breakage . DNA damage triggers activation of caspase-3 and -7 and cleavage of the enzyme PARP (Poly ADP ribose polymerase), leading to apoptosis and a loss of mitochondrial membrane potential. Amrubicin, like all anthracyclines, intercalates into DNA and produces reactive oxygen free radicals via interaction with NADPH, which causes cell damage . Compared with doxorubicin, another member of the anthracycline drug class, amrubicin binds DNA with a 7-fold lower affinity and therefore, higher concentrations of amrubicin are necessary to promote DNA unwinding . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Amrubicin belongs to the class of organic compounds known as tetracenequinones. These are polyaromatic hydrocarbon derivatives containing a tetracyclic cycle made up of four linearly fused benzene rings, one of which bears two ketone groups at position 1 and 4, classified under the direct parent group Tetracenequinones. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Naphthacenes class, specifically within the Tetracenequinones subclass.

Categories:

Amrubicin is categorized under the following therapeutic classes: Anthracyclines and Related Substances, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, Carbohydrates, Cytotoxic Antibiotics and Related Substances, Glycosides, Naphthacenes. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Amrubicin include:

• Water Solubility: not soluble in water, but soluble in DMSO
• Melting Point: 172-174
• Boiling Point: 717.8
• logP: 2.64